König Corinna, Ivanisenko Nikita V, Ivanisenko Vladimir A, Kulms Dagmar, Lavrik Inna N
Translational Inflammation Research, Medical Faculty, Otto von Guericke University (OvGU), Magdeburg, Magdeburg, Germany.
Institute of Cytology and Genetics, Novosibirsk, Russia.
Commun Biol. 2025 Jan 3;8(1):4. doi: 10.1038/s42003-024-07409-6.
Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIP, in the caspase-8/c-FLIP heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis. However, the effects of FLIPinB action in combination with other cell death inducers have only just begun to be elucidated. Here, we show that FLIPinB enhances the cell death in pancreatic cancer cells induced by combinatorial treatment with DL, gemcitabine and Mcl-1 inhibitor S63845. Further, we found that these effects are mediated via an increase in the complex II assembly. Collectively, our study shows that targeting the caspase-8/c-FLIP heterodimer in combination with the other drugs in pancreatic cancer cells is a promising direction that may provide a basis for further therapeutic strategies.
外在凋亡网络由死亡配体（DL）介导的procaspase-8激活驱动。最近，我们开发了首个小分子FLIPinB，它特异性靶向半胱天冬酶-8/细胞凋亡抑制蛋白（c-FLIP）异二聚体中外在凋亡的关键调节因子——蛋白c-FLIP。我们已经表明，FLIPinB可增强DL诱导的半胱天冬酶-8活性和细胞凋亡。然而，FLIPinB与其他细胞死亡诱导剂联合作用的效果才刚刚开始得到阐明。在此，我们表明，FLIPinB可增强由DL、吉西他滨和Mcl-1抑制剂S63845联合处理诱导的胰腺癌细胞死亡。此外，我们发现这些效应是通过复合物II组装的增加介导的。总的来说，我们的研究表明，在胰腺癌细胞中靶向半胱天冬酶-8/c-FLIP异二聚体并与其他药物联合使用是一个有前景的方向，可能为进一步的治疗策略提供基础。
